This is a 371 of International Application PCT/EP00/10528, filed Oct. 25, 2000 and published in English, the contents of which are incorporated herein by reference.
This invention relates to heterocyclic compounds, in particular to thiazoles and imidazopyridines and to their use for treating TNFxcex1 and IL-1 mediated diseases such as rheumatoid arthritis and diseases of bone metabolism, e.g. osteoporosis.
Accordingly the present invention provides a compound of formula I 
wherein Nu is a heterocyclic nucleus selected from a thiazole in which the R1, R2 and R3 substituents are disposed as indicated below 
and an imidazo[4,5-b]pyridine in which the R1, R2 and R3 substituents are disposed as indicated below 
wherein
R1 is pyrimidyl or pyridyl;
X is xe2x80x94NR6xe2x80x94Yxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94,
where R6 is H, C1-C4alkyl, C3-C8cycloalkyl, C3-C8cycloalkylC1-C3alkyl, C6-C18aryl, C3-C18heteroaryl, C7-C19aralkyl or C4-C19heteroaralkyl, and xe2x80x94Yxe2x80x94 is C1-C4alkylene or a direct bond;
R2 is phenyl, optionally substituted by one or more substituents, each of which is independently selected from
halo,
CF3,
cyano,
amido or thioamido which is optionally mono- or di-N-substituted by C1-C4alkyl or the N atom of which forms a 5-7 membered heterocyclic ring optionally containing an additional hetero atom selected from O, S or N which N is optionally C1-C4alkyl C1-C4alkylcarbonyl or C1-C4alkylthiocarbonyl substitued,
carboxylate or thiocarboxylate optionally in the form of an optionally halo-substituted C1-C10alkoxy, C2-C10alkenoxy, C2-C10alkynoxy, C3-C7cyclalkoxy, C5-C7cycloalkenoxy, aryloxy, arylalkoxy, heteroaryloxy or heteroarylalkoxy ester,
optionally mono- or di-C1-C4alkyl-substituted-C0-C1alkyl optionally C1-C4alkyl- or C3-C5 cycloalkyl-substituted-carbonyl or -thiocarbonyl,
optionally halo-substituted-C1-C4alkoxy, C2-C4alkenoxy, C2-C4alkynoxy, C3-C5cycloalkoxy or C3-C5cyclothioalkoxy,
optionally halo substituted C1-C4 alkyl,
oxycarbonyl or optionally Nxe2x80x94C1-C4alkyl-substituted aminocarbonyl both of which are optionally C1-C4alkyl or C3-C5cycloalkyl substituted (including thiocarbonyl analogues thereof),
optionally mono- or di-C1-C4alkyl-substituted-C0-C1alkylamine which is optionally mono- or di-Nxe2x80x94C1-C4 alkyl substituted,
optionally mono- or di-C1-C4acyl-substituted-C0-C1alkyl optionally Nxe2x80x94C1-C4alkyl-substituted amino-carbonyl or -thiocarbonyl,
optionally Nxe2x80x94C1-C4alkyl-substituted amino-sulphinyl or -sulphonyl optionally substituted by
optionally mono- or di-Nxe2x80x94C1-C4alkyl-substituted amino,
a nitrogen atom which form a heterocyclic ring of 5 to 7 members optionally containing an additional heteroatom selected from O, S or N which N is optionally C1-C4alkyl C1-C4alkylcarbonyl or C1-C4alkylthiocarbonyl substitued, or
sulphinyl or sulphonyl optionally substituted by
optionally halo-substituted-C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl,
optionally mono- or di-C1-C4alkyl-substituted amino,
a nitrogen atom which form a heterocyclic ring of 5 to 7 members optionally containing an additional heteroatom selected from O, S or N which N is optionally C1-C4alkyl C1-C4alkylcarbonyl or C1-C4alkylthiocarbonyl substitued;
R3 is H, amino, C1-C10alkyl, C3-C10cycloalkyl, C3-C18heterocycloalkyl, C6-C18aryl, or C3-C18heteroaryl each of which is optionally substituted by up to 4 substituents separately selected from C1-C4alkyl, halogen, halo-substitued-C1-C4alkyl, hydroxy, C1-C4alkoxy, C1-C4alkylthio, C6-C18aryl, C3-C18 heteroaryl, C6-C18arylC1-C4alkyl, C3-C18 heteroarylC1-C4alkyl, C3-C18heterocycloalkyl or optionally mono- or di-C1-C4alkyl substituted amino or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally a further hetero atom selected from O, S or N, all of which are further optionally substituted halo, hydroxy, C1-C4alkyl, C1-C4alkoxy or C1-C4alkoxycarbonyl;
R4 is C1-C10alkyl, C6-C18aryl, C3-C18heteroaryl, or C3-C12cycloalkyl optionally substituted by up to 3 substituents separately selected from C1-C4alkyl, halogen, halo-substitued-C1-C4alkyl, hydroxy, C1-C4alkoxy, C1-C4alkylthio, optionally mono- or di-C1-C4alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom selected from O, S or N,
and pharmaceutically-acceptable and -cleavable esters thereof and acid addition salts thereof.
Above and elsewhere in the present description the terms halo or halogen denote I, Br, Cl or F.
Above and elsewhere in the present description the terms such as xe2x80x9cC3-C18heteroaryl, C4-C19heteroaralkyl and C3-C18heterocycloalkylxe2x80x9d denote heteroaryl, heteroaralkyl or heterocycloalkyl substituents comprising at least 3 ring atoms, at least one of which is a hetero atom, e.g. N, O or S, and which in the case of C4-C19heteroaralkyl groups are attached via an alkylene moiety comprising at least 1 carbon atom.
In particular embodiments the invention provides a compound of formula II 
wherein
Z is N or CH;
X is xe2x80x94NR6xe2x80x94Yxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94,
where R6 is H, C1-C4alkyl, C3-C8cycloalkyl, C3-C8cycloalkylC1-C3alkyl, C6-C18aryl, C3-C18heteroaryl, C7-C19aralkyl or C4-C19heteroaralkyl, and xe2x80x94Yxe2x80x94 is C1-C4alkylene or a direct bond;
R2xe2x80x2 is phenyl, optionally substituted by one or more substituents, each of which is independently selected from halo, CF3, cyano, amido or thioamido, carboxylate or thiocarboxylate, C1-C4alkoxy, C1-C4alkyl, or NH2 which is optionally mono- or di-C1-C4 alkyl substituted;
R3xe2x80x2 is H, C1-C10alkyl, C3-C10cycloalkyl, C3-C18heterocycloalkyl, C6-C18aryl, or C3-C18heteroaryl each of which is optionally substituted by up to 4 substituents separately selected from C1-C4alkyl, halogen, halo-substitued-C1-C4alkyl, hydroxy, C1-C4alkoxy, C1-C4alkylthio, or optionally mono- or di-C1-C4alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom selected from O, S or N;
R4xe2x80x2 is C6-C18aryl, C3-C18heteroaryl, or C3-C12cycloalkyl each of which is optionally substituted by up to 4 substituents separately selected from C1-4alkyl, halogen, halo-substitued-C1-4alkyl, hydroxy, C1-4alkoxy, C1-4alkylthio, or optionally mono- or di-C1-C4alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom selected from O, S or N,
and pharmaceutically-acceptable and -cleavable esters thereof and acid addition salts thereof.
When R3xe2x80x2 is aryl, it is preferably heteroaryl, e.g. pyridyl (e.g. 4-pyridyl) or pyrazyl, each optionally substituted, e.g. by 2 substituents, separately selected from C1-C4alkyl, halogen, hydroxy, C1-C4alkoxy, or optionally mono- or di-C1-C4alkyl substituted amino.
When R3xe2x80x2 is cycloalkyl it is preferably C3-C8, especially C5-C6cycloalkyl (e.g. cyclohexyl), optionally substituted, e.g. by 1 or 2 substituents, separately selected from C1-C4alkyl, halogen, hydroxy, C1-C4alkoxy, or optionally mono- or di-C1-C4alkyl substituted amino.
When R3xe2x80x2 is heterocycloalkyl it is preferably N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom, e.g. N or O, and is optionally substituted, e.g. by 1 or 2 substituents, separately selected from C1-C4alkyl, halogen, hydroxy, C1-C4alkoxy, or optionally mono- or di-C1-C4alkyl substituted amino.
When R4xe2x80x2 is aryl it is preferably phenyl. When Rxe2x80x24 is cycloalkyl, it is preferably C3-C7 cycloalkyl, e.g. cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl. Rxe2x80x24 may be unsubstituted or substituted, conveniently mono-substituted, e.g. phenyl conveniently meta or para substituted, by halogen, C1-C4alkyl, halo-substituedC1-C4alkyl, C1-C4alkoxy, hydroxy or optionally mono- or di-C1-C4alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom selected from O, S or N.
When Y is C1-C4 alkylene, it is preferably C1-C2 alkylene, and is optionally substituted, e.g. by C1-C4alkyl (e.g. methyl), halogen, hydroxy, C1-C4alkoxy, or amino.
More preferably Rxe2x80x22 is phenyl substituted, preferably mono- or di-substituted, by halogen or a halogen-containing group, e.g. 4-fluorophen-1-yl, or 3-CF3, 3-Cl, or 3,4-difluoro substituted phenyl.
More preferably Rxe2x80x23 is H, C1-C6alkyl, phenyl, pyridyl, morpholinyl, piperidyl, piperazyl, or optionally mono- or di-C1-4alkyl substituted amino, each of which is optionally substituted, e.g. by up to 2 substituents, separately selected from C1-C4alkyl, halogen, hydroxy, C1-C4alkoxy, or optionally mono- or di-C1-C4alkyl substituted amino.
Preferably X is xe2x80x94NHxe2x80x94Yxe2x80x2xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, where Yxe2x80x2 is xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94 or a direct bond
Thus in preferred embodiments the invention provides a compound of formula IIxe2x80x2
wherein
R4xe2x80x3 is phenyl or C3-C7cycloalkyl each of which is optionally mono-substituted by halogen, C1-C4alkyl, C1-C4alkoxy, hydroxy, trihalomethyl or optionally mono- or di-C1-C4alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom selected from O, S or N;
R10 is halogen, cyano, amido, thioamido, amino or C1-C4alkyl;
R3xe2x80x3 is H, C1-C4alkyl, phenyl, pyridyl, morpholinyl, piperidyl, piperazyl, or optionally mono- or di-C1-4alkyl substituted amino, each of which is optionally substituted, e.g. by up to 2 substituents, separately selected from C1-C4alkyl, halogen, hydroxy, C1-C4alkoxy, or optionally mono- or di-C1-C4alkyl substituted amino;
Z is N or CH and
Xxe2x80x3 is xe2x80x94NHxe2x80x94Yxe2x80x2xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, where Yxe2x80x2 is xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94 or a direct bond,
and pharmaceutically-acceptable and -cleavable esters thereof and acid addition salts thereof.
Preferably R4xe2x80x3 is unsubstituted or monosubstituted by halogen, C1-C4alkyl (e.g. methyl), C1-C4alkoxy (e.g. methoxy), hydroxy or CF3.
Preferably R10 is halogen, e.g. F.
Preferably Xxe2x80x3 is xe2x80x94NHxe2x80x94Yxe2x80x2 where Yxe2x80x2 is xe2x80x94CH(CH3)xe2x80x94.
The Invention includes the following compounds:
4-(4-Fluorophenyl)-5-(2-[1-(S)-phenylethyl]amino-4-pyrimidinyl)-2-(4-methyl-piperidine-1-yl)thiazole;
4-(4-Fluorophenyl)-5-(2-[1-(S)-phenylethyl]amino-4-pyrimidinyl)-2-(4-NH-piperidine-1-yl)thiazole;
4-(4-Fluorophenyl)-2-(4-methylpiperidine-1-yl)-5-(2-[cyclopropyl-methyl]amino-4-pyridinyl)thiazole and
4-(4-Fluorophenyl)-2-(4-NH-piperidine-1-yl)-5-(2-(1-(S)-phenylethyl)amino-4-pyridinyl)thiazole;
The novel thiazoles of the invention, in particular the compounds of formulae II and IIxe2x80x2 and the specific compounds listed above are hereinafter referred to xe2x80x9cAgents of the Inventionxe2x80x9d.
Agents of the Invention of formula IIxe2x80x3
wherein R3xe2x80x3, R5xe2x80x3, R10 and Z are as previously defined and Xxe2x80x2xe2x80x3 is xe2x80x94NHxe2x80x94, may be prepared by reacting the corresponding precursor compound of formula III or IIIxe2x80x2
wherein R3xe2x80x2 and R10 are as previously defined, with the corresponding R4xe2x80x3xe2x80x94NH2 derivative. For example, the reaction may be carried out by refluxing the reactants in an organic solvent, e.g. dichloroethane, e.g. in the presence of diethoxytrifluoroborane. Thereafter, if desired, the compound of Formula IIxe2x80x3 obtained may be converted into a further compound of Formula IIxe2x80x3 or otherwise treated as required.
The precursor compound of formula III may be prepared by controlled oxidation of the corresponding 5(2-methylthio-4-pyrimidinyl)-4-phenythiazole, e.g. employing an oxidising agent such as mCPBA (meta chloroperbenzoic acid), conveniently in an organic solvent such as methylene chloride. The corresponding 5(4-pyrimidinyl/pyridinyl)-4-phenylthiazole compound may be prepared by contacting the corresponding acetophenone precursor compound of formula IV or IVxe2x80x2
wherein R10 is as defined above, with a corresponding thioamide of formula R3xe2x80x2C(S)NH2, typically at elevated temperature. The compounds of formula IV and IVxe2x80x2 may be prepared by bromination of the corresponding acetophenone, e.g. 2-(2-methylthio-4-pyrimidinyl)acetophenone. The acetophenone precursor may be prepared by reacting the corresponding N-methoxy-N-methylbenzamide with the corresponding pyrimidine, e.g. 4-methyl-2-(methylthio)pyrimidine, for instance in a THF containing organic solvent with cooling.
Thus in a further aspect the invention includes a process for the preparation of a compound of formula IIxe2x80x3
wherein R3xe2x80x3, R4xe2x80x3, R10 and Z are as previously defined and Xxe2x80x2xe2x80x3 is xe2x80x94NHxe2x80x94, which comprises reacting the corresponding precursor compound of formula III or IIIxe2x80x2
wherein R3xe2x80x3 and R10 are as previously defined, with the corresponding R4xe2x80x3xe2x80x94NH2 amine, and thereafter, if desired, converting the compound of formula IIxe2x80x3 obtained into a further compound of formula IIxe2x80x3 or a pharmaceutically-acceptable and -cleavable ester thereof or acid addition salt thereof.
In further particular embodiments the invention provides a compound of formula V 
wherein
R11 is pyrimidyl;
X is xe2x80x94NR6xe2x80x94Yxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94,
where R6 is H, C1-C4alkyl, C3-C8cycloalkyl, C3-C8cycloalkylC1-C3alkyl, C6-C18aryl, C3-C18heteroaryl, C7-C19aralkyl or C4-C19heteroaralkyl, and xe2x80x94Yxe2x80x94 is C1-4alkylene or a direct bond;
R12 is phenyl, optionally substituted by one or more substituents, each of which is independently selected from
halo,
CF3,
cyano,
amido or thioamido which is optionally mono- or di-N-substituted by C1-C4alkyl or the N atom of which form a 5-7 membered heterocyclic ring optionally containing an additional hetero atom selected from O, S or N which N is optionally C1-C4alkyl C1-C4alkylcarbonyl or C1-C4alkylthiocarbonyl substitued,
carboxylate or thiocarboxylate optionally in the form of an optionally halo-substituted C1-C10alkoxy, C2-C10alkenoxy, C2-C10alkynoxy, C3-C7cyclalkoxy, C5-C7cycloalkenoxy, aryloxy, arylalkoxy, heteroaryloxy or heteroarylalkoxy ester,
optionally mono- or di-C1-C4alkyl-substituted-C0-C1alkyl optionally C1-C4alkyl- or C3-C5 cycloalkyl-substituted-carbonyl or -thiocarbonyl,
optionally halo-substituted-C1-C4alkoxy, C2-C4alkenoxy, C2-C4alkynoxy, C3-C5cycloalkoxy or C3-C5cyclothioalkoxy,
optionally halo substituted C1-C4 alkyl, oxycarbonyl or optionally Nxe2x80x94C1-C4alkyl-substituted aminocarbonyl both of which are optionally C1-C4alkyl or C3-C5cycloalkyl substituted (including thiocarbonyl analogues thereof),
optionally mono- or di-C1-C4alkyl-substituted-C0-C1alkylamine which is optionally mono- or di-Nxe2x80x94C1-C4 alkyl substituted,
optionally mono- or di-C1-C4alkyl-substituted-C0-C1alkyl optionally Nxe2x80x94C1-C4alkyl-substituted amino-carbonyl or -thiocarbonyl,
optionally Nxe2x80x94C1-C4alkyl-substituted amino-sulphinyl or -sulphonyl optionally substituted by
optionally mono- or di-Nxe2x80x94C1-C4alkyl-substituted amino,
a nitrogen atom which form a heterocyclic ring of 5 to 7 members optionally containing an additional heteroatom selected from O, S or N which N is optionally C1-C4alkyl C1-C4alkylcarbonyl or C1-C4alkylthiocarbonyl substituted, or
sulphinyl or sulphonyl optionally substituted by
optionally halo-substituted-C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl,
optionally mono- or di-Nxe2x80x94C1-C4alkyl-substituted amino,
a nitrogen atom which form a heterocyclic ring of 5 to 7 members optionally containing an additional heteroatom selected from O, S or N which N is optionally C1-C4alkyl C1-C4alkylcarbonyl or C1-C4alkylthiocarbonyl substituted;
R13 is H, amino, C1-C10alkyl, C3-C10cycloalkyl, C3-C18heterocycloalkyl, C6-C18aryl, or C3-C18heteroaryl all optionally substituted by up to 4 substituents separately selected from C1-C4alkyl, halogen, halo-substitued-C1-C4alkyl, hydroxy, C1-C4alkoxy, C1-C4alkylthio, C6-C18aryl, C3-C18heteroaryl, C6-C18arylC1-C4alkyl, C3-C18heteroarylC1-C4alkyl, C3-C18heterocycloalkyl or optionally mono- or di-Nxe2x80x94C1-C4alkyl substituted amino all of which are optionally substituted by halo, hydroxy, C1-C4alkyl, C1-C4alkoxy or C1-C4alkoxycarbonyl;
R14 is C1-C10alkyl, C6-C18aryl, C3-C18heteroaryl, or C3-C12cycloalkyl optionally substituted by up to 3 substituents separately selected from C1-C4alkyl, halogen, halo-substitued-C1-C4alkyl, hydroxy, C1-C4alkoxy, C1-C4alkylthio, optionally mono- or di-Nxe2x80x94C1-C4alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom selected from O, S or N,
and pharmaceutically-acceptable and -cleavable esters thereof and acid addition salts thereof.
R11 is preferably 4-pyrimidyl.
When R13 is alkyl it is C1-C10alkyl, preferably C1-C6alkyl, optionally substituted, preferably with one or two substituents separately selected from hydroxy, C1-C4alkoxy, amino optionally mono- or disubstituted by C1-C4alkyl or N-heterocyclyl containing from 5 to 7 ring and optionally containing a further hetero atom (e.g. O, S or N).
When R13 is aryl or heteroaryl either of which is optionally substituted by up to 4 substituents, R13 may comprise one of the customary aryl or heteroaryl substituents in the art and may be substituted as is customary in the art; for instance as defined for the substituent R3 of WO 93/03297. For instance, R13 may comprise a phenyl, pyridyl or pyrimidyl, substituent optionally substituted by up to 5 substituents separately selected from C1-C4alkyl, halogen, halo-substituted C1-C4alkyl, hydroxy, C1-C4alkoxy, or optionally mono- or di-C1-C4alkyl substituted amino.
When R13 is substituted amino it may be substituted by one or two substitutents independently selected from C1-C4alkyl, C6-C18aryl, C3-C18 heteroaryl, C6-C18arylC1-C4alkyl, C3-C18 heteroarylC1-C4alkyl, all of which are optionally substituted by halo, hydroxy, C1-C4alkyl, C1-C4alkoxy or C1-C4alkoxycarbonyl.
When R13 is cycloalkyl it is preferably C3-C8, especially C5-C6cycloalkyl (e.g. cyclohexyl), optionally substituted, preferably with up to 2 substituents separately selected from C1-C4alkyl, halogen, hydroxy, C1-C4alkoxy, or optionally mono- or di-C1-C4alkyl substituted amino.
When R13 is heterocycloalkyl it is preferably N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom selected from O, S or N, optionally substituted, e.g. by up to 2 substituents, selected from halogen, hydroxy, alkoxy, or optionally mono- or di-C1-C4alkyl substituted amino. For instance, R13 may be an optionally substituted morpholino, piperazyl or piperidyl substituent.
When R14 is aryl it is preferably phenyl. When R14 is cycloalkyl, it is preferably C3-C7 cycloalkyl, e.g. cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl. R14 may be unsubstituted or substituted, conveniently mono-substituted, e.g. phenyl conveniently meta or para substituted, by halogen, C1-C4alkyl, halo-substitued C1-C4alkyl, C1-C4alkoxy, hydroxy, optionally mono- or di-Nxe2x80x94C1-C4alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom selected from O, S or N.
When xe2x80x94Yxe2x80x94 is C1-C4 alkylene, it is preferably C1-C2 alkylene, and is optionally substituted, e.g. by C1-C4alkyl (e.g. methyl), halogen, hydroxy, C1-C4alkoxy, or amino.
Preferably R12 is phenyl substituted with 1-3 substituents, preferably mono-substituted, selected from halogen, CN, halo-substituted alkyl, e.g. CF3, C1-C4alkyl, or C1-C4alkoxy. Most preferably R2 is phenyl mono-substituted by halogen, e.g. 4-flurophenyl.
In particular embodiments R13 is pyridyl, pyrimidyl, piperazyl, piperidyl, xe2x80x94NR9R10, xe2x80x94CH2OH, xe2x80x94CH2NR15R16, xe2x80x94CH2CH2R15R16, or Hetxe2x80x94C1-4alkyl-,
wherein
R9 and R10 are separately selected from H, C1-C4alkyl, C6-C18aryl, C3-C18 heteroaryl, C6-C18arylC1-C4alkyl, C3-C18heteroarylC1-C4alkyl all of which are optionally substituted by halo, C1-C4alkyl, C1-C4alkoxy, C1-C4alkoxycarbonyl,
R15 and R16 are separately selected from H or C1-C4alkyl, and
Het is N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom (e.g. O, S or N).
Preferably X is xe2x80x94NHxe2x80x94Yxe2x80x2xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, where Yxe2x80x2 is xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94 or a direct bond. Most preferably X is NHxe2x80x94Yxe2x80x3xe2x80x94, where Yxe2x80x3 is xe2x80x94CH(CH3)xe2x80x94 or a direct bond.
Thus in preferred embodiments the invention provides a compound of formula Vxe2x80x2
wherein
R14xe2x80x2 is phenyl or C3-C7cycloalkyl each of which is optionally mono-substituted by halogen, C1-C4alkyl, C1-C4alkoxy, hydroxy, trihalomethyl optionally mono- or di-Nxe2x80x94C1-C4alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom selected from O, S or N;
R10 is halogen, CF3, C1-C4alkyl or C1-C4alkoxy;
R13xe2x80x2 is pyridyl, pyrimidyl, piperazinyl, piperidinyl, NR9R10, xe2x80x94CH2OH, CH2NR15R16, xe2x80x94CH2CH2R15R16, or Hetxe2x80x94C1-C4alkyl-, wherein
R9 and R10 are separately selected from H, C1-C4alkyl, C6-C18aryl, C3-C18 heteroaryl, C6-C18arylC1-C4alkyl, C3-C18heteroarylC1-C4alkyl all of which are optionally substituted by halo, hydroxy, C1-C4alkyl, C1-C4alkoxy, C1-C4alkoxycarbonyl,
R11 and R12 are separately selected from H or C1-C6alkyl, and
Het is N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom (e.g. O, S or N)
Xxe2x80x3 is xe2x80x94NHxe2x80x94Yxe2x80x2xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, where Yxe2x80x2 is xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94 or a direct bond,
and pharmaceutically-acceptable and -cleavable esters thereof and acid addition salts thereof.
Preferably R14xe2x80x2 is phenyl or cyclopentyl, cyclobutyl or cyclopropyl.
Preferably R10 is halogen.
Preferably Xxe2x80x3 is xe2x80x94NHxe2x80x94Yxe2x80x3 where Yxe2x80x3 is xe2x80x94CH(CH3)xe2x80x94 or a direct bond.
The Invention includes the following compounds:
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(piperidino-N-2-ethyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(N,N-diethylamino-N-2-ethyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(morpholino-N-2-ethyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(isopropylamino-N-2-ethyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(pyrrolidino-N-2-ethyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(3-pyridyl)imidazo[4,5-]pyridine; 
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(4-pyridyl)imidazo[4,5-b ]pyridine;
2-(4-Fluorophenyl)-1-(2-(1-(S)-phenylethyl)amino-4-pyrimidinyl)-5-aminoimidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-aminoimidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-(1-(S)-phenylethyl)amino-4-pyrimidinyl)-5-(4-NH-1-piperazinyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(4-NH-1-piperazinyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclobutylamino-4pyrimidinyl)-5-(4-NH-1-piperazinyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopropylamino-4-pyrimidinyl)-5-(4-NH1-piperazinyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-(1-(S)-phenylethyl)amino-4-pyrimidinyl)-5-(4methyl-1-1-piperazinyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-clopentylamino-4-pyrimidinyl)-5-(4-methyl-1-piperazinyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclobutylamino-4-pyrimidinyl)-5-(4-methyl-1-piperazinyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopropylamino-4-pyrimidinyl)-5-(4-methyl-1-piperazinyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-(1-(S)-phenylethyl)amino-4-pyrimidinyl)-5-(4-(2-hydroxy-2-methyl)propyl-1-piperazinyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(4-(2-hydroxy-2-methyl)propyl-1-piperazinyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclobutylamino-4-pyrimidinyl)-5-(4-(2-hydroxy-2-methyl)propyl-1-piperazinyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopropylamino-4-pyrimidinyl)-5-(4-(2-hydroxy-2-methyl)propyl-1-piperazinyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(4-piperidinyl)imdazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(1-methyl-4-piperidinyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(1-(2-hydroxy-2-methyl)propyl-4-piperidinyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(benzylamino)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)1-(2-cyclopentylamino-4-pyrimidinyl)-5-(morpholino)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(3-fluorophenyl amino)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(pyridyl-4-amino)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(1-ethoxycarbonyl piperidine-4-amino)imidazo[4,5-b]pyridine, and
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(piperidine-4-amino)imidazo[4,5-b]pyridine.
The novel imidazopyridines of the invention, in particular the compounds of formulae V and Vxe2x80x2 and the specific compounds listed above are hereinafter also referred to as xe2x80x9cAgents of the Inventionxe2x80x9d.
It will be appreciated that certain Agents of the Invention may contain at least 1 assymetric carbon atom; for instance when Y is substituted alkylene, e.g. when Yxe2x80x3 is xe2x80x94CH(CH3)xe2x80x94 for the compounds of formula IIxe2x80x2 or Vxe2x80x2 above. The resulting diastereomers and enantiomers are encompassed by the instant invention. Preferably, however, e.g. for pharmaceutical use in accordance with the invention, the compounds of formula I, are provided in pure or substantially pure epidermic form, e.g. as compositions in which the compounds are present in a form comprising at least 90%, e.g. preferably at least 95% of a single epimer (i.e. comprising less than 10%, e.g. preferably less than 5% of other epimeric forms). Preferred epimeric compounds of formula I are described hereinafter in the Examples.
The Agents of the Invention which comprise free hydroxyl groups may also exist in the form of pharmaceutically acceptable, physiologically cleavable esters, and as such are included within the scope of the invention. Such pharmaceutically acceptable esters are preferably prodrug ester derivatives, such being convertible by solvolysis or cleavage under physiological conditions to the corresponding Agents of the Invention which comprise free hydroxyl groups. Suitable pharmaceutically acceptable prodrug esters are those derived from a carboxylic acid, a carbonic acid monoester or a carbamic acid, advantageously esters derived from an optionally substituted lower alkanoic acid or an arylcarboxylic acid.
Agents of the Invention may also exist in the form of pharmaceutically acceptable salts, and as such are included within the scope of the invention. Pharmaceutically acceptable salts include acid addition salts with conventional acids, for example, mineral acids, e.g., hydrochloric acid, sulfuric or phosphoric acid, or organic acids, for example, aliphatic or aromatic carboxylic or sulfonic acids, e.g., acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic, maleic, fumaric, hydroxymaleic, pyruvic, pamoic, methanesulfonic, toluenesulfonic, naphthalenesulfonic, sulfanilic or cyclohexylsulfamic acid; also amino acids, such as argiline and lysine. For compounds of the invention having acidic groups, for example, a free carboxy group, pharmaceutically acceptable salts also represent metal or ammonium salts, such as alkali metal or alkaline earth metal salts, e.g., sodium, potassium, magnesium or calcium salts, as well as ammonium salts, which are formed with ammonia or suitable organic amines.
Agents of the Invention of Formula Vxe2x80x3
wherein R11, R12, R14 and X are as previously defined and R13xe2x80x3 is xe2x80x94CH2xe2x80x94CH2NR15R16 or xe2x80x94CH2xe2x80x94CH2xe2x80x94Het wherein R15, R16 and Het are as defined above may be prepared by reacting a corresponding vinyl precursor compound of formula VI 
wherein R11, R12, R14 and X are as previously defined, with the corresponding amine of formula HNR15R16 or N-heterocycloalkyl ring compound. For instance the reaction may be carried out by refluxing the reactants, e.g. in acetic acid, followed by treatment with a mild base, e.g. Na2CO3.
The precursor compound of formula VI may be prepared by reacting the corresponding 5-chloro-imdazopyridine of formula VII 
wherein R11, R12, R14 and X as are as previously defined, with a vinylating agent. For instance the chloro compound of formula VII is reacted with vinyltributylstannane in the presence of PdCl2(PPh3)2 in xylene at elevated temperature, e.g. 160xc2x0 C., under an inert atmosphere.
Agents of the Invention of formula V, wherein R13 is aryl or heteroaryl may be prepared from chloroprecursor compounds of formula VII, as defined above, by arylation or heteroarylation. For instance the compound of formula VII is heated with the corresponding trialkylstannyl-aryl or -heteroaryl, e.g. tributylstannylaryl- or trimethylstannyl-aryl or -heteroaryl, compound e.g. to about 150xc2x0 C. under an inert atmosphere.
Agents of the Invention of formula V, wherein R13 is xe2x80x94N-heterocycloalkyl, xe2x80x94NH-aryl, xe2x80x94NH-heteroaryl, xe2x80x94NH-heterocycloalkyl, xe2x80x94NHxe2x80x94(C1-C4alkyl)-heterocycloalkyl, xe2x80x94NHxe2x80x94(C1-C4alkyl)-aryl, xe2x80x94NHxe2x80x94(C1-C4alkyl)-heteroaryl, or xe2x80x94NHxe2x80x94(C1-C4alkyl)-heterocycloalkyl may be prepared from chloroprecursor compounds of formula VII, as defined above, by coupling with the corresponding N-heterocycloalkyl compound or amine. The coupling reaction may carried out using Buchwald chemisty. For instance, to a solution of the chloroprecursor compound of formula VII and a suitable ligand, e.g. BINAP, in an inert organic solvent such as xylene is added the N-heterocycloalkyl compound or amine together with an organic base, e.g. sodium tertiary butylate, and the reaction mixture heated, e.g. to 160xc2x0 C. for 10 minutes under argon; after which the product may be recovered by pouring the reaction mixture onto water and solvent extraction, e.g. with TBME.
The compounds of formula VII in which X is xe2x80x94NHxe2x80x94 may be prepared by reacting the corresponding methylsulphinyl compound of formula VIII 
wherein R11 and R12 are as previously defined, with the corresponding amine of formula R14xe2x80x94NH2. For instance, the reactants are mixed and heated, e.g. to 80xc2x0 C. for 1 h.
The methylsulphinyl compound of formula VIII prepared by oxidation of the corresponding methylthio compound of formula IX. 
wherein R11 and R12 are as previously defined; for instance, by treating the compound of formula IX in solution, e.g. CH2Cl2/HOAc solution, with mCPBA, e.g. at 0xc2x0 C. for 30 min., followed by treatment with mild base, e.g. Na2CO3.
The methylthio compound of formula IX may be prepared by coupling the corresponding 1-H-imidazopyridine compound of formula X 
wherein R12 is as defined above, with 2-methylthio-4-iodopyrimidine. For instance, KN(TMS)2 solution, e.g. in toluene, is added at 0xc2x0 C. to a solution of X, e.g. in DMF with mixing, and 2-methyl-4-iodopyrimidine solution e.g. in toluene, is added and the reaction mixture heated e.g. at 120xc2x0 C. for 20 h.
The compound of formula X may be prepared by coupling 2,3-diamino-6-chloropyridine with the corresponding acid of formula R12COOH; for instance, by treating a mixture of the reactants with polyphosphonic acid e.g. at 150xc2x0 C. for 6 h, followed by neutralisation e.g. with cold concentrated aqueous NH3.
Compounds of formula V in which R13 is NH2 may be prepared by reacting the corresponding methyl sulphinyl compound of formula VIIIxe2x80x2
wherein R11 and R12 are as previously defined, with the corresponding amine of formula R14xe2x80x94NH2, for instance, as described above for the compound of formula VI. The compound of formula VIIIxe2x80x2 and precursors therefor may be prepared by analogy with the compound of formula VIII and the precursors thereof; for instance, as described above.
Agents of the Invention which are 5-(4-NH-1-piperazyl)imidazopyridines of formula V in which R13 is piperazyl and precursors therefor may be prepared by analogy to the preparation of the compound of formula VIIIxe2x80x2 and the precursors thereof. Conveniently the free nitrogen atom of the piperazine ring is protected e.g. with a tert. butoxycarbonyl residue, during precursor preparation as appropriate. 5-(4-NH-1-piperazyl)imidazopyridines of formula I may be converted to 5-(4-substituted piperazyl)imidazopyridine Agents of the Invention as desired; for instance, as hereinafter described in the Examples.
Accordingly in a further aspect the invention provides a process for the production of
(i) an Agent of the Invention of formula Vxe2x80x3
wherein R11, R12, R14 and X are as previously defined and R13xe2x80x3 is xe2x80x94CH2xe2x80x94CH2NR15R16 or xe2x80x94CH2xe2x80x94CH2xe2x80x94Het wherein R15, R16 and Het are as previously defined comprising reacting a corresponding vinyl precursor of formula VI 
wherein R11, R12, R14 and X are as previously defined with the corresponding amine of formula HNR15R16 or N-heterocycloalkyl ring compound;
(ii) an Agent of the Invention of formula V wherein R13 is Aryl or heteroaryl comprising arylation or heteroarylation of a compound of formula VII 
wherein R11, R12, R14 and X are as previously defined;
(iii) an Agent of the Invention of formula V wherein R13 is xe2x80x94N-heterocycloalkyl, xe2x80x94NH-aryl, xe2x80x94NH-heteroaryl, xe2x80x94NH-heterocycloalkyl, xe2x80x94NHxe2x80x94(C1-C4alkyl)-heterocycloalkyl, xe2x80x94NHxe2x80x94(C1-C4alkyl)-aryl, xe2x80x94NHxe2x80x94(C1-C4alkyl)-heteroaryl, or xe2x80x94NHxe2x80x94(C1-C4alkyl)-heterocycloalkyl comprising coupling a corresponding chloroprecursor compound of formula VII, as defined above, with the corresponding N-heterocycloalkyl compound or amine;
(iv) an Agent of the Invention of formula V in which R13 is xe2x80x94NH2, comprising reacting the corresponding methyl sulphinyl compound of formula VIIIxe2x80x2
wherein R11, and R12 are as previously defined, with the corresponding amine of formula R14xe2x80x94NH2, and
(v) an Agent of the Invention of formula V in which R13 is piperazinyl, comprising reacting a corresponding methylsulphinyl compound of formula VIIIxe2x80x3
wherein R11 and R12 are as previously defined and P is an N protecting group, with the corresponding amine of formula R14xe2x80x94NH2.
The synthesis of Agents of the Invention is further described in the following Examples.